Prospects for a Peptide Vaccine for Human Lupus
Prospects for a Peptide Vaccine for Human Lupus
The requirements for a peptide vaccine have been listed in the context of other autoimmune diseases. We have found that certain endogenous peptide epitopes in histones from nucleosomes can induce regulatory mechanisms that inhibit major components of pathogenic autoimmune response in established disease in lupus prone mice in vivo, and in lupus patients' cells in vitro. Extensive studies in mouse models and recent work with lupus patients' cells have shown that the histone peptide epitopes have the requirements for a vaccine, as follows:
Desirable Qualities of a Peptide Vaccine for Lupus
The requirements for a peptide vaccine have been listed in the context of other autoimmune diseases. We have found that certain endogenous peptide epitopes in histones from nucleosomes can induce regulatory mechanisms that inhibit major components of pathogenic autoimmune response in established disease in lupus prone mice in vivo, and in lupus patients' cells in vitro. Extensive studies in mouse models and recent work with lupus patients' cells have shown that the histone peptide epitopes have the requirements for a vaccine, as follows:
The nucleosomal histone peptides are nontoxic, as they are endogenous, derived from body's own proteins which are used to 'educate' the immune system during development. The epitopes are naturally processed and unaltered peptide ligands (UPLs) derived from nucleosomes of apoptotic cells that are expressed in the thymus and bone marrow during ontogeny of the immune system and, therefore, unlike artificially altered peptide ligands (APLs), the histone peptides are not associated with anaphylactic/allergic reactions. Indeed recognition of histone peptide epitope in the thymus generates Tregs even in lupus-prone mice, indicating that the default response to the peptide epitopes is regulatory;
The epitopes are effective in vivo at very low doses, and by subcutaneous or intranasal administration in suppressing pathogenic autoantibody production and renal inflammation in animal models of lupus. Only 1 μg (0.34 nM) of the histone peptide epitope/s is effective in low-dose tolerance therapy of mice with lupus, which would be equivalent to 0.2–2 mg range in lupus patients. Such low doses would lessen the chance of stimulating autoimmune effector T cells;
The epitopes are highly soluble as they contain many charged residues, and they are rapidly absorbed systemically after subcutaneous injection. By rendering plasmacytoid dendritic cells tolerogenic as soon as the peptides reach the lymphoid organs, the peptides generate long-lasting, antigen-specific Tregs that suppress disease pathology. Therefore, short half life or decay of the epitopes is not a concern as they are taken up by tolerogenic antigen-presenting cell (APC). Moreover, the stable, autoantigen-specific Tregs generated in vivo by the peptide therapy can also block accelarated lupus disease upon adoptive transfer;
The histone peptide epitopes induce cross-reactive, 'tolerance spreading' or linked tolerance to other pathogenic T- and B-cell autoepitopes, thus suppressing the broad spectrum of autoimmune response in lupus, but they do not suppress responses to exogenous antigens;
The peptides have both MHC class II and nested class I determinants so that they could genenrate both CD4 and CD8 Tregs, similar to the potent Tregs generated after stem cell transplantion that keep lupus patients in long-term immunologic remission;
The peptides are recognized directly by antinuclear autoantibodies so that they could tolerize autoimmune B cells of lupus as well;
Importantly, the epitopes are recognized by autoimmune T and B cells of all lupus patients tested irrespective of their HLA type;
The peptide epitopes are effective even when the autoimmune disease and nephritis are already established;
The peptides generate Tregs in lupus patients' cells even in the presence of commonly used drugs, hydroxychloroquine or steroids, or lupus serum containing type I interferon (IFN)-inducing immune complexes;
The peptides also have direct effect on autoimmune B cells and dendritic cells in lupus, in addition to generation of Tregs, as the peptides could suppress autoantibody production by patients' cells to baseline levels irrespective of the degree of Treg induction and suppressed type I IFN gene signature;
Even healthy people can have their regulatory mechanisms against nuclear autoantigens boosted by the histone peptides suggesting the possibility of vaccinating apparently healthy people at risk for lupus with these peptides;
Histone peptide therapy would be cheaper than many of the biologics.
